Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurological disease that is characterized by denervation and the loss of motor neurons that control voluntary muscle movement. Currently, there is no cure for ALS and no effective treatment to halt, or reverse, the progression of this devastating disease with unclear etiology. There is an urgent need for the development of novel effective therapies for ALS that preserve both axons and motor neuron cell bodies. In the past 22 years only two drugs have been approved, and they provide only very minor slowing of disease progression, if at all, and their benefits remain controversial. The discovery of neurotrophic factors that prevent the loss of motor neurons in cellular and animal models of ALS and axon injury has raised the hopes for effective treatments. Perhaps the most promising candidate was ciliary neurotrophic factor (CNTF), a potent neurotrophic factor in the interleukin-6 (IL-6) family of cytokines that has been shown to prevent not only the loss of motor neurons, but also axonal degeneration. Signaling of human CNTF is mediated primarily via high-affinity-binding to a tripartite receptor complex containing CNTF alpha receptor (CNTFR). In addition, human CNTF can bind and activate an alternative receptor in which CNTFR is substituted by the IL-6 alpha receptor (IL-6R). Despite the promising preclinical data in animal models, subsequent large clinical trials with systemic delivery of recombinant CNTF protein in human ALS patients have been unsuccessful, due to its poor pharmacokinetic profile, patients developing an immune response to CNTF, and adverse side effects via promiscuous binding to IL-6R, which activated the acute phase response. It is our central hypothesis that selective small-molecule agonists of CNTFR can be identified that have the potential to solve these problems that caused the failure of clinical trials. Our long-term goal is to address the need for potent and selective small-molecule CNTFR agonists for systemic treatment of patients with ALS. While small-molecule mimics have been developed successfully for BDNF and other neurotrophic factors, the most promising agonist for CNTFR is a mutated version of the protein with increased selectivity for CNTFR, but unresolved problems of short half-life and immunogenicity. Here we propose a collaboration to develop a cell-based high throughput screen (HTS) and follow-on biological assays to discover and validate small molecules that protect motor neuron function and survival by specifically activating CNTFR but not IL-6R complexes. Our specific aims are 1) to develop an HTS assay for selective CNTFR agonists and 2) optimize secondary assays in neurons. In the second phase we would 1) conduct HTS of a large and diverse library for selective CNTFR agonists, 2) characterize promising therapeutic agents, and 3) perform focused medicinal chemistry approaches to develop early lead compounds. These studies are likely to identify novel small molecules with great potential for future development into therapeutics for ALS and other neurodegenerative disorders.